Download Usher Syndrome (3-6% of childhood deafness)

Usher Syndrome and
Progressive Hearing Loss
Margaret A. Kenna, MD, MPH
Otolaryngology and Communication Enhancement
Boston Children’s Hospital
Professor of Otology and Laryngology
Harvard Medical School
Harvard
Medical
School
Harvard Medical School Center
for Hereditary Deafness
Boston
Children’s
Hospital
Seven steps to treatment for an Inherited
Disease (Bill Kimberling)
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Find the disease gene
Correlate genotype with phenotype
Find or develop animal models
Elucidate the disease mechanism
Find or develop and effective treatment in the
animal model
Screen the human population to identify people
who might benefit
Test the treatment in these people
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Orphan diseases, small numbers
Incidence of Hearing Loss in
Newborns
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Profound bilateral 1-2/1000 births
Another 1-2/1000 with significant HL
33 babies born every day with significant
permanent hearing loss
>12,000 babies per year in the U.S.
The most common congenital sensory
impairment
How Common is Usher Syndrome
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Prevalence: 1/16-20,000 US
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With more genes more common
Estimated 16,000-25,000 individuals in the US
with USH
Up to 10 % of congenitally deaf children with
USH1
3-6% of all congenitally hearing impaired
children with USH1, 2, 3
Carrier frequency 1/70 (varies by gene, mutation
and population)
Usher Syndrome
Hearing Loss Vestibular
System
Type I
Congenital
profound
Type II
Congenital
mild-severe
sloping;
progressive
Progressive
later onset
Type III
Retinitis
Pigmentosa
Congenital
Onset prebalance
puberty
problems; absent
caloric responses
Normal
Onset in
teens-20s
Variable, often
Variable
progressive
onset
balance problems
How to make the Usher
Diagnosis
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Test the hearing
Test the vision
Test the balance
Test the genes
Test olfaction?
Look at brain?
Audiologic Features
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USH 1 - bilateral congenital profound SNHL
USH 2 - bilateral moderate SNHL; may
progress
USH 3 – May be of later onset, may progress
All patients initially appear non-syndromic
except for the hearing loss
Not all patients with mutations in the same
Usher gene have the same presentation
Usher Gene Phenotype
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Most genes cause congenital/childhood onset HL
followed by RP
USH2A also causes non-syndromic RP
MYO7A, USH1C, CDH23, PCDH15, WHRN may
cause hearing loss only
Change in olfaction (sense of smell)
Cognition
Sperm motility
Cerebral atrophy
Ataxia
Registry
FREQUENCY IN HERTZ (Hz)
125
250
500
750
1000
1500
2000
3000
4000
6000
8000
KEY
-10
R
L
HEARING LEVEL (HL) IN DECIBELS (dB)
0
10
USH 1B
20
AC (AIR)
UNMASKED
MASKED
30
BC (BONE)
40
UNMASKED
MASKED
50
SOUND
FIELD
60
S
SPEECH
AUDIOMETRY
R
L
70
80
SDT
90
SRT
100
110
120
Tympanograms: normal
SPEECH
DISCRIM.
(WORD
RECOG.)
8% 4%
USH1B
2 year old female
with 2 novel MYO7A
mutations
USH2A
8 year old male
with USH2A and
normal vision; ERG
not done. Child’s
maternal grandmother
and siblings have USH2
clinically, but child has a
novel mutation, so unclear
what effect this will have
on his vision and ERG
Adult with USH 2A who presented with “non-syndromic” RP
5/7/2010
USH3
12/2/08
14 year old female from Cape Verde with
progressive SNHL and RP, and normal
balance. Dad and Dad’s brother with the
same. Homozygous CLARIN1 mutations.
Routine Eye Exams in Children with SNHL:
Can you diagnose Usher Syndrome?
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16 children
All have two pathogenic USH mutations
“Routine” eye exams did not pick up USH in any
patients who were pre-symptomatic (i.e. not night
blind)
9/16 had diagnosis made by genetic testing; youngest
was 8 months
Age of walking not entirely predictive of USH 1
patients, and was normal in USH 2 and USH 3
Kenna, Fulton, Hansen, Rehm, et al, 2010
How could the hearing loss
progress
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Many genes
Result in many proteins
Many forms of each protein
Interaction depends on many things besides just
making the protein
Environment
Locus name
Genome Location
Gene name
Gene Protein Product
Animal Model
USH1B
11q13.5
MYO7A
Myosin 7A
Shaker 1/Mariner
USH1C
11p15.1-p14
USH1C
Harmonin
Deaf circler
USH1D
10q22-q22
CDH23
Cadherin 23
Waltzer/deaf waddler
USH1E
21q21.1
Unknown
Unknown
none
USH1F
10q21.1
PCDH15
Protocadherin 15
Ames waltzer
USH1G
17q25.1
USH1G
Usher Syndrome Type
1G protein
USH1H
15q22-23
USH1H
Unknown
USH 1K
10p11.21-q21.1
Unknown
Unknown
USH2A
1q41
USH2A
Usherin
USH2C
5q13
GRP98
G protein-coupled Receptor
98
USH2D
9q32-34
DFNB31
Cask-interacting protein
USH3A
3q21-q25
CLRN1
Clarin-1
USH2A
modifier
10q24.31
PDZD7
PDZD7
USH3B
5q31.3
HARS
Diagram of the sensory cells in the inner ear and retina.
Kremer H et al. Hum. Mol. Genet. 2006;15:R262-R270
© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions,
please email: [email protected]
Outline of the Usher proteins and their different isoforms.
Kremer H et al. Hum. Mol. Genet. 2006;15:R262-R270
© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions,
please email: [email protected]
The Usher protein network.
Kremer H et al. Hum. Mol. Genet. 2006;15:R262-R270
© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions,
please email: [email protected]
What else could be causing the
hearing loss?
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CMV
Other genetic
Funny inner ear anatomy
Other causes of hearing and vision loss
Prematurity
 Alstrom syndrome
 Two different causes for hearing loss and vision
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Prenatal Infections
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TORCHES
Toxoplasmosis 1:8000; 0-26% have HL,
decreased if treated promptly
Rubella (one reported case in 2006; but baby can
get if mother vaccinated during pregnancy)
CMV 1/100-200 births
Herpes 1:2500-10,000, but HL very rare unless
the baby has obvious systemic infection
Syphilis 11/100,000 (2002)
Inflammatory mediators pre/peri natal
Hearing Loss due to Perinatal Causes
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NICU
PPHN
 Ototoxicity
 Sepsis
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Hyperbilirubinemia
ECMO
Ototoxicity
Sepsis
Extreme prematurity
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Auditory dyssynchrony
Postnatally Acquired Infections
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Bacterial meningitis
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Parvovirus B-19 (Fifth’s disease)
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Marked decrease since HIB, Prevnar®
N. meningitidis vaccination
Associated with autoimmune hearing loss
Mumps (2007, 800/100,000 US)
Measles (2005, <1/1,000,000)
Lyme - Facial nerve dysfunction more common than
hearing loss
HIV
EBV
Ramsay-Hunt (Varicella zoster)
Otitis media/cholesteatoma
Hearing Loss due to Postnatal Causes
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Trauma
Head trauma
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Noise
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Sports
Altercations
MVA
Child abuse
MP3
Hunting
Radiation
Surgery
Autoimmune
Postnatally acquired causes of HL
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Ototoxicity
Aminoglycosides
Mitochondrial genes confer increased susceptibility
 Children with cystic fibrosis
 Transplants
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Macrolides
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Diuretics
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Azithromycin, clarithromycin, erythromycin
Furosemide (Lasix®)
Retinoic acid
Aspirin, acetaminophen with codeine, other
Epidemiology of CMV
1% of all live births
 10-15% of babies with congenital CMV
are symptomatic
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 75%
of these will have CNS symptoms
 65% of these will have SNHL
Of asymptomatic babies 5-10% develop
SNHL
 Over 50% have progressive hearing loss
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Radiological features
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Polymicrogyria
Cerebral calcification
White matter loss
Ventricular dilatation
Cystic changes
Overall, abnormal in 54%
Genetics of Hearing Loss: Non-syndromic
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~140 loci for Non-Syndromic HL
70 recessive (DFNB)
 55 dominant (DFNA)
 5 X-linked (DFN)
 2 modifier (DFNM)
 Several Mitochondrial (MTN)
 1 Y-linked (DFNY)
 1 Auditory neuropathy (AUN)
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Van Camp G, Smith RJH. http://webho1.ua.ac.be/hhh 3.5.09
Syndromic Hearing Loss
Syndrome
Inheritance
Prevalence**
Treacher-Collins
AD
Common
Pendred/LVAS
AR
Very common
Waardenburg
AD
Common
Usher
AR
Common
BOR Syndrome
AD
Common
Norrie Disease
XL, AR
Uncommon
Alport Syndrome
XL, AD, AR
Uncommon
Stickler Syndrome
AD
Uncommon
Jervell & Lange-Nielsen AR
Rare
**relative to other syndromic forms of hearing loss
Genetic causes of later onset and
progressive HL
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Dominant genes associated with presbycusis
GJB2 (Connexin 26): 50% progression rate
SLC26A4 (PDS): Associated with enlarged
vestibular aqueduct
Turner’s syndrome (XO): mid-frequency dip
Otosclerosis: later onset and progressive
Usher’s syndrome, types 2 and 3 esp.
Mitochondrial genes: may cause HL with or
without aminoglycosides
FREQUENCY IN HERTZ (Hz)
125
250
500
750
1000
1500
2000
3000
4000
6000
8000
KEY
-10
HEARING LEVEL (HL) IN DECIBELS (dB)
0
10
R
35delG / 35delG
AC (AIR)
Age 15 months
UNMASKED
20
L
MASKED
30
BC (BONE)
40
UNMASKED
MASKED
50
SOUND
FIELD
60
SPEECH
AUDIOMETRY
R
L
70
80
SDT
90
SRT
100
110
120
S
Tympanograms: normal
SPEECH
DISCRIM.
(WORD
RECOG.)
25 30
Pendred Syndrome
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Enlarged vestibular aqueducts
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Goiter resulting from abnormal organification of
iodine in the thyroid
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10-20% of pts with AU EVA have PDS
If have Pendred syndrome, will have abnormal
perchlorate washout studies but euthyroid labs
SLC26A4 (PDS) causes both Pendred’s
Syndrome and recessive non-syndromic SNHL
(DFNB4)
Normal cochlear partition
-Incomplete partition
-Modiolar deficiency
-“Mondini”
Incomplete partitioning
Testing for Usher Syndrome
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Clinical diagnosis
Hearing loss
 RP
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Electroretinography
Balance
 ??/olfaction, cognition
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Genetic diagnosis
Single gene testing
 Multiple gene testing
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Genetic Testing for Usher
Syndrome
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Conservative approach:
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Less conservative approach:
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HL with retinal abnormalities (positive ERG test or
pigmentary changes)
Profound congenital hearing loss with delayed
walking
Even less conservative approach
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Test children with non-profound losses if Cx26 (and
possibly Cx30) negative and CT/MRI normal
Genetics of Hearing Loss
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2 pathogenic mutations in a known USH gene
2 mutations of unclear significance in an USH
gene (VUS)
1 pathogenic mutation and one VUS
1 pathogenic mutation in two different USH
genes (digenic)
Otochip®
Otogenome®
Otoscope®
Insurance
OtoChip™ for Hearing Loss and Usher Syndrome
Nonsyndromic
Syndromic
Cx26 Testing
Aminoglycosides
Mitochondrial
12S rRNA
tRNA ser
Family Hx
X-linked
POU3F4
19 genes - 430 amplicons
~70,000 bases
Appropriate Gene(s)
No Family Hx
Usher Syndrome
MYO7A SANS
USH1C USH2A
CDH23 VLGR1
PCDH15 USH3
Dominant
Recessive
MYO6
ACTG1
DSPP
TECTA
EYA4
MYO7A
COL11A2
POU4F3
TMC1
MYO1A
MYO7A
MYO15
PDS
OTOF
TMPRSS3
TECTA
GJB6
CLDN14
TMC1
STRC
DIAPH1
WFS1
GJB3
KCNQ4
GJB6
DFNA5
MYH9
COCH
TFCP2L3
TMIE
CDH23
USH1C
OTOA
MYO3A
PCDH15
WHRN
ESPN
MYO6
PRES
JLNS
KCNE1
KCNQ1
Treatment for the Hearing Loss
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Hearing Aids
Cochlear implants
Molecular therapy for the hearing loss
Gene therapy
 Different size genes
 Different viral vectors
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Cochlear Implants
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Bilateral severe to profound
Infants and young children
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Early diagnosis of USH helps with decision making
Progressive hearing loss
Effect on balance
Who Needs Genetic Counseling
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Families/patients being tested for hearing loss
genes (pre-testing)
Families/patients being given genetic results
There may be a greater need for genetic
counseling when test results are negative
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Patients may not understand that the cause of
hearing loss could still be genetic
Summary
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If definitely USH, hearing loss can progress
If not certain USH, try and confirm a diagnosis
Rarely, could be more than one diagnosis
Manage the hearing loss according to degree
Manage the diagnosis according to what makes
sense
Thank
you!